Table 3.
Gene function and literature description of novel candidate genes
| Family | Gene | Gene function | Relevant human phenotype association(s) | Gene expression* | Animal model** | Gene constrain metrics (90% CI)*** | Patient phenotype |
|---|---|---|---|---|---|---|---|
| FIN4 | NTRK1 | Ligand for neurotrophins, regulate development of the central and the peripheral nervous systems (Bibel 2000) | Insensitivity to pain, congenital, with anhidrosis (AR) (OMIM #191315) | Expressed in brain (mainly caudate, putamen) | Homozygous lethal (mice; IMPC) |
LOF: o/e = 0.43 (0.29—0.66); pLI = 0.88 missense: o/e = 0.87 (0.8—0.94); Z = 1.45 |
Moderate to severe ID, Lennox epilepsy, unclear speech, neuropsychiatric symptoms |
| FIN21 | SYPL1 | Integral membrane protein present in synaptic vesicles (OMIM #616665) | Paralog SYPL2 gene has been associated with morbid obesity and depression (Jiao et al. 2015; Shi et al. 2011) | Ubiquitously expressed in neuronal and non-neuronal tissues; high expression in the spinal cord | Behavioral, craniofacial, skeletal, reproductive system abnormalities (mice; IMPC). Mice lacking paralog Sypl2 have been reported to display reduced body weight(Jiao et al. 2015) |
LOF: o/e = 0.36 (0.17—0.82); pLI = 0.05 missense: o/e = 0.89 (0.77—1.04); Z = 0.45 |
Metopic suture, delayed neurodevelopment and bone maturation, obesity, panic disorder |
| FIN23 | ITPR2 | Intracellular calcium release channels (Futatsugi 2005) | AD and AR variants in paralog ITPR1 cause Gillespie syndrome (OMIM #147265) | Ubiquitously expressed in neuronal and non-neuronal tissues | Exocrine dysfunction in ITPR2 or ITPR3 double knock-out mice, difficulties in nutrient digestion, early mortality (Futatsugi 2005) |
LOF: o/e = 0.5 (0.42—0.61); pLI = 0 missense: o/e = 0.72 (0.69—0.76); Z = 3.71 |
Neurological and ophthalmological abnormalities, deafness |
| FIN27 | ZKSCAN1 | Cellular proliferation and differentiation; regulates GABA type-A receptor expression in the brain; GABA is the major inhibitory neurotransmitter in the mammalian brain (Mulligan et al. 2012) | Variants in GABA type-A receptor can cause epileptic encephalopathy and susceptibility to various epilepsy types (Ella et al. 2018) | Ubiquitously expressed in neuronal and non-neuronal tissues | ND |
LOF: o/e = 0.12 (0.06—0.32); pLI = 0.97 missense: o/e = 0.67 (0.6—0.75); Z = 2.12 |
Syndromic phenotype with severe ID |
| FIN32 | ZFR | Important in axon guidance, RNA transport and localization in neurons (Kjærgaard et al. 2015) | Previously been suggested as a candidate gene in spastic paraplegia (Novarino et al. 2014) | Ubiquitously expressed in neuronal and non-neuronal tissues | ND |
LOF: o/e = 0.05 (0.02—0.13); pLI = 1 missense: o/e = 0.52 (0.47—0.57); Z = 4.09 |
Mild ID, slender habitus, neuropsychiatric symptoms |
| FIN45 | POLR2F | Encodes a subunit of RNA polymerase II; important in synthesizing messenger RNA in eukaryotes (OMIM # 604414) | Variants in paralog POLR2A cause neurodevelopmental syndromes characterized by profound infantile-onset hypotonia, and developmental delays (OMIM # 180660) | Restricted expression to brain and nerve tissues | Metabolic/immune/hematopoietic system abnormalities (mice; IMPC) |
LOF: o/e = 0.42 (0.22—0.88); pLI = 0.01 missense: o/e = 0.73 (0.59—0.9); Z = 0.89 |
Profound ID, infantile spasms, never learned to speak or walk, increased saliva production |
| FIN47 | DNAH3 | Ciliary and flagellar motility (OMIM #603334) | Suggested candidate gene for ID (Kochinke et al. 2016) | Expressed primarily in long and testis | ND |
LOF: o/e = 0.69 (0.6—0.8); pLI = 0 missense: o/e = 1 (0.96—1.03); Z = 0.03 |
Profound ID, congenital hydrocephalus, no speech, nystagmus, dysmorphic ear lobes |
| FIN-ID3 | ERGIC3 | A component of ERGIC, which mediates the transport from the endoplasmic reticulum to the Golgi (OMIM # 616971) | Suggested candidate gene for ID (Monies et al. 2019) | Ubiquitously expressed in neuronal and non-neuronal tissues | ND |
LOF: o/e = 0.46 (0.3—0.75); pLI = 0 missense: o/e = 0.71 (0.62—0.81); Z = 1.55 |
Mild ID, cleft lip |
| FIN-AIC2 | KIF1B | transports mitochondria and synaptic vesicle precursors; involved in apoptosis (OMIM # 605995) | AD Charcot-Marie-Tooth disease, type 2A1; susceptibility to tumors (OMIM # 605995) | Preferential expression in brain and skeletal muscle | Homozygous lethal, abnormal embryo size, head shape, limb morphology (mice; IMPC) |
LOF: o/e = 0.1 (0.06—0.17); pLI = 1 missense: o/e = 0.68 (0.63—0.72); Z = 3.6 |
Epilepsy, severe ID, coloboma |
*Based on the Genotype-tissue expression consortium (GTEx) data (https://www.gtexportal.org/home/), unless referenced otherwise. ** Based on the International Mouse Phenotyping Consortium (IMPC; https://www.mousephenotype.org/), unless referenced otherwise. ***Gene constrain metrics (90% confidence interval), based on the gnomAD database (https://gnomad.broadinstitute.org/): o/e: The ratio of the observed / expected number of loss-of-function or missense variants in that gene. A low o/e value indicates the gene is under stronger selection. pLI: A higher score (maximum 1) indicates more intolerance of protein-truncating variants the transcript appears to be (pLI ≥ 0.9 as an extremely intolerant). Missense Z-score: Higher (more positive) Z scores indicate that the transcript is more intolerant of variation (more constrained)
LOF: Loss-of-function; ND: not determined